We (and others) have identified a series of corepressor and coactivator proteins that physically associate with nuclear receptors, recruit additional proteins, and help mediate transcriptional repression or activation. Many signals that impact on nuclear receptor function manifest their effects through changes in corepressor and coactivator recruitment or function. We propose to continue our research into how the actions of nuclear receptors are mediated through these coregulators. We will address specific aspects of 5 broad questions: Specific Aim 1. How can otherwise closely-related isoforms of the same nuclear receptor display very different transcriptional properties: elucidation of the divergent transcriptional properties of thyroid hormone receptors beta 1 and beta 2. Specific aim 2. How do newly recognized N-terminal receptor interaction domains (nRID) in SMRT and N- CoR contribute to the actions of these corepressors? Specific Aim 3. How are the composition and transcriptional regulatory properties of the corepressor complex regulated by phosphorylation? Specific Aim 4. How does alternative mRNA splicing of SMRT and N-CoR customize their molecular properties? Specific Aim 5. How does alternative mRNA splicing of SMRT and N-CoR contribute to their biological functions? These experiments seek both to enhance our understanding of how nuclear receptors operate in mediating normal physiology, and to improve our knowledge of how aberrations in coregulator function lead to disease. Relevance: The proposed studies will improve our knowledge of how important hormones function in healthy individuals. They also will reveal how disruptions to these functions can lead to disease, and may provide clues resulting in improved treatments.